ABSTRACT Basic investigations postulate that an imbalance between neurotransmitters regulating the stress (corticotropin releasing factor, CRF, norepinephrine, orexin, vasopressin and dynorphin) and anti-stress systems (nociceptin and neuropeptide Y, NPY) underlie negative reinforcement and relapse in addiction. NPY is one such neuropeptide transmitter that exerts anti-stress effects in the brain. Basic investigations support a role for increased NPY transmission in counteracting an overactive CRF system to block anxiety and stress- induced relapse in alcoholism. The lack of PET radiotracers to measure neurotransmitters that modulate stress is a major barrier to evaluating some of the most promising theories and novel therapeutic strategies advanced by basic investigations in human addicts. The proposed research aims to develop and characterize a specific radioligand that targets the NPY Y1 receptor system. The ability to non-invasively measure this receptor subsystem in humans will lead to insights related to the role of negative reinforcement and relapse in addiction. To date, no human studies have characterized the brain stress and anti-stress systems involved in negative reinforcement and relapse. The development of a specific NPY Y1 receptor ligand suitable for human research applications will be a significant step in characterizing a major component of the brain anti-stress system in addiction. The availability of a NPY Y1 PET tracer to use in humans will also be of interest to the study of other psychiatric and medical disorders such as anxiety, obesity, hypertension, epilepsy and certain carcinomas in which NPY Y1 has been implicated